Early Clinical Experiences with Nintedanib in 3 Tertiary Interstitial Lung Disease Centres Hannah Toellner (5th year medical student)*, Dr Nazia Chaudhuri*, W. Beswick , M.G. Crooks , C. Donaldson , I. Forrest , S.P Hart , C. Leonard*, M. Major , A.J. Simpson *University Hospital of South Manchester (UHSM) Hull and East Yorkshire Hospitals NHS Trust Newcastle Upon Tyne Hospitals NHS Trust WEBSITE: www.northwestipfmanchester.weebly.com TWITTER: North West ILD Unit FACEBOOK: North West and Greater Manchester Interstitial Lung Disease Unit

Conflict of Interest Disclosure I received an educational grant from Boehringer Ingelheim to attend the ERS Conference, London 2016

IPF: An increasing problem Rising incidence in UK 5% year on year increase in mortality Limited treatments Nintedanib and pirfenidone reduce rate of FVC decline Patient access scheme NICE approval in April 2013 and January 2016 Patients eligible if FVC 50-80% (1) 1. Navaratnam V, Fleming KM, West J, Smith CJ, Jenkins RG, Fogarty A, et al. The rising incidence of idiopathic pulmonary fibrosis in the U.K. Thorax. 2011;66(6):462-7.

Evidence base for nintedanib Richeldi et al. (TOMORROW) (2) 150mg twice daily Slows rate of annual FVC decline by 68.4% Incidence of acute exacerbations 2.4 vs 15.7 per 100 patient years Smaller decrease in quality of life score Richeldi et al. (INPULSIS I and II) (3) Reduction in annual FVC decline (p<0.001) 2. Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079-87. 3.Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-82.

Aim Report real world data using nintedanib Focus on: Type and frequency of adverse events (AEs) Impact of AEs on treatment continuation

Methods Multi-centre retrospective observational study Data collection from clinical letters Patient inclusion criteria: Commenced treatment as part of patient access scheme Started between December 2014-January 2016 MDT diagnosis of IPF Ineligible for or intolerant to pirfenidone Follow up monthly for 6 months 3 monthly thereafter

Demographics 187 patients Average age: 71 years±8 Average pre-treatment FVC: 81.1%±19.8 Average length of treatment: 236 days The average length of treatment was 258 days±138 (range 12-492) at UHSM, 230 days±132 (range 6-457) at Hull and 37 days±14 (range 28-56) at Newcastle.

Adverse events are common 723 AEs in total Average 3.9 AEs per individual patient

Adverse events are predominantly gastrointestinal

Adverse events are predominantly gastrointestinal Adverse Event (AE) Percentage of Patients experiencing AE Percentage of Patients experiencing AE from INPULSIS I Percentage of Patients experiencing AE from INPULSIS II Diarrhoea 49.7% 61.5% 63.2% Nausea 36.4% 22.7% 26.1% Reduced appetite 23.5% 8.4% 12.8% Myocardial Infarction 0.5% 1.6% 1.5% Abnormal LFTs 9.6% 4.9% 5.2%

Most AEs can be managed without treatment discontinuation Patients commonly experience AEs with nintedanib but encouraging that most of these are tolerated by patients. 64% of all reported AEs in our study were successfully managed with no change to treatment regimen and 21% by dose reduction In fact, 71% cases of diarrhoea led to no change in treatment at all and only 8% resulted in discontinuation. Similarly, the INPULSIS trials showed a less than 5% discontinuation rate with nintedanib because of diarrhoea (22). This reflects that AEs can usually be managed adequately without impacting long term treatment adherence.   The measures taken to alleviate AEs in both our real world study and the INPULSIS trials were similar. Patients could reduce their dose to 100mg twice daily or temporarily stop treatment while the AE resolved. In our study counselled to take the medication with food to help with symptoms of nausea and were commonly prescribed loperamide for diarrhoea. Proton pump inhibitors, H2 histamine receptor antagonists and anti-emetics were also concomitantly advised for some patients. Gross observation and interpretation of clinical letters at UHSM suggests that loperamide is effective at reducing diarrhoea in the majority of IPF patients and that patients who take the medication with food are less nauseous. In addition, there are indications from clinic letters at UHSM to suggest that significant AEs do not appear in many patients until they have been on treatment with nintedanib for a couple of months. However, this needs to be proven in another study in order to draw any firm conclusions

Nintedanib is well tolerated Our discontinuation rate: 21% INPULSIS-I: 25% INPULSIS-II: 24%

Discussion Strengths Our patient cohort: Older age Wider range of lung function More co-morbidities Limitations Smaller patient cohort (187 vs 1066) Reporter bias Researcher bias Missing data Cross over of AEs and IPF symptoms

Conclusion 1. AEs with nintedanib are common 2. Acceptable AE profile and no signal of increased risk of cardiovascular events or bleeding 3. Tolerated by the majority of patients

Acknowledgements Nazia Chaudhuri C. Leonard (University Hospital of South Manchester) W. Beswick, M.G. Crooks, S.P Hart, M. Major (Hull and East Yorkshire Hospitals NHS Trust) C. Donaldson, I. Forrest, A.J. Simpson (Newcastle Upon Tyne Hospitals NHS Trust)